Substituted 2-aminoisonicotinic acid hydrazides



United States Patent 3,131,194 SUBSTITUTED Z-AMINOISONICOTINIC ACID HYDRAZIDES William F. Bruce, Havertown, and Alan D. Lourie, Bala- Cynwyd, Pa., assignors to American Home Products Corporation, New York, N.Y., a corporation of Delaware No Drawing. Filed Dec. 14, 1962, Ser. No. 244,586

12 Claims. (Cl. 260-295) This invention relates to novel substituted Z-aminoisonicotinic acid hydrazides and to a process for the production thereof.

The novel compounds made available by the present invention exhibit sedative and analgesic activity. Unlike other hydrazine compounds, the novel compounds of this invention do not appreciably inhibit monoamine oxidase.

The compounds sought to be patented are represented by the following formula:

('JONHNHR N// NH wherein R represents a lower alkyl radical, preferably having from 2 to 9 carbon atoms; a .cycloalkyl radical, preferably having trom to 8 carbon atoms; or a l-cycloalkylalkyl radical, preferably having from 4 to 8 carbon atoms.

The novel compounds made available by the present invention are prepared by the process illustrated by the following equation:

oONHNH,

' NH N/ 2 R! A 2)n C=0 G3 Br! CONHN=C (CH2). CONHN=C l V I RI! NH, L NH,

(IIIA) (IIIB) \[m 1/ x. 1! CONHNHR Np NH,

In the above formulas, n ranges from 4 to 7, R represents a lower alkyl radical having from one to six carbon .toms or a cycle alkyl radical having from 3 to 5 carbon atoms in its ring, R" represents hydrogen or a lower alkyl 1 radical having from one to 2 carbon atoms; and R has the meaning previously set forth.

In practising the process outlined above, Z-aminoisonicotinic acid hydrazide (II) is condensed with the appropriate carbonyl starting material to form the correspending Schifi base um), (111B), which is then catalytically hydrogenated with, for example, hydrogen and a suitable catalyst such as platinum oxide.

Formation of the Schifi base preferably is carried out 3,131,194 Patented Apr. 28, 1964 by refluxing the react-ants in .a solvent inert to the reaction, such as anhydrous ethanol, for a period ranging from 15 minutes, for the lower molecular weight carbonyl reactants, to around 24 hours, for the more sterically hindered reactants. The Schitr' bases formed by the previously described step are then partially dissolved in an inert anhydrous solvent, such as ethanol, methanol or 2&- rnethoxyethanol. A noble metal catalyst or its oxide is added to the resulting mixture and the whole is agitated with hydrogen in a suitable hydrogenation vessel at room temperature until no more hydrogen is absorbed by the hydrazide. Where it is noted that absorption has ceased and that less than the theoretical amount of hydrogen has been absorbed, the hydrogenation step is interrupted; additional catalyst is introduced into the reaction mass and hydrogenation is resumed and continued until no more hydrogen is absorbed.

The starting 2-aminois0nicotinic acid hydrazide conveniently may be prepared by warming ethyl 2-amino isonicotinate with hydrazine hydrate.

The following examples, in which temperatures are in degrees centigrade, represent the best mode of carrying out the present invention.

EXAMPLE 1 Z-aminoisonicotinic acid hydrazide.--Ethyl 2-aminoisonicotinate (9.9 g., 0.0597 mole) was heated on a steam bath with -12 ml. hydrazine hydrate for five to ten minutes. The product was washed with absolute ethanol. The yield was 8.5 g. (93.7%), M.P. 186l90.

EXAMPLE 2 Z-aminoisonicotinic acid 2-is0pr0pylidenehydrazide. 2-aminoisonicotinic acid hydrazide (5.0 g., 0.0331 mole) was refluxed for one half hour in ml. absolute acetone. After cooling, 5.8 g. (91.8%) product was filtered oft, M.P. 199-201 Analysis.Calcd. for C H N O: C, 56.23; H, 6.30; N, 29.14. Found: C, 56.19; H, 6.12; N, 29.11.

Z-amz'noisonicotinic acid 2-isopropylhydrazide.-2 aminoisonicotinic acid 2-isopropylidenehydrazide (8.0 g., 0.0417 mole) was dissolved in 200 ml. absolute methanol with 50 0 mg. platinum oxide, and the mixture shaken with hydrogen in a Parr apparatus at room temperature for about two hours. The hydrogen absorption was approximately theoretical. The catalyst was filtered oil and the solvent evaporated in vacuo. Recrystallization of the residue from acetone gave 3.7 g. (39.6%) product, M.P. 198. The mixed melting point with starting material was 17419l. A second crop yielded 1.3 g. (total yield: 61.8%).

Analysis.-Calcd for C H N O: C, 55.65; H, 7.27; N, 28.84. Found: C, 55.92; H, 7.48; N, 28:71.

EXAMPLE 3 Z-aminoisonictinic acid Z-valerylia'enehydrazine.2- aminoisonicotinic acid hydrazide (6.3 g., 0.0414 mole) was refluxed with 3.6 g. (0.0418 mole) valeraldehyde and 100 ml. absolute ethanol for one hour. The solution Was cooled and 4.4 g. (48.3%) product filtered otf, M.P. l83- 186. A second crop yielded 1.6 g. (total yield: 65.8%).

Analysis.Calcd. for C H N O: C, 59.98; H, 7.32; N, 25.44. Found: C, 59.85; H, 7.28; N, 25.65.

Z-aminoisonicotinic acid Z-valerylhydrazide.2-aminoisonicotinic acid 2-valerylidenehydrazide (4.9 g., 0.0223 mole) was dissolved in 200 ml. absolute methanol with 500 mg. platinum oxide, and the mixture shaken with hydrogen in a Parr apparatus at room temperature for about two and three quarter hours. The hydrogen ab sorption was slightly greater than the theoretical amount. The catalyst was filtered oil and the solvent evaporated in vacuo. The crude product was recrystallized from Water containing a little ethanol to yield 2.9 g. (58.7%

M.P. 171-173". The mixed melting point with starting material was 165168. A second crop yielded 0.5 g. (total yield: 68.7%).

Ahalysis.Ca1cd. for C H N O: C, 59:43; 25.21. Found: C, 59.21; H, 7.97; N, 25.18.

EXAMPLE 4 2 aminoisonicotinic acid 2 cyclopentylidenehydrazide.2-aminoisonicotinic acid hydrazide (3.5 g., 0.023 mole) was refluxedfor fifteen minutes with 12 ml. cyclopentanone and 50 ml. absolute ethanol. The mixture was cooled and 4.65 g (92.7%) product-was filtered ofi, M.P. 255-260 (dec.).

Analysis.Calcd. for C H N O C, 60.53; H, 6.47; N, 25.67. Found: C, 59169; H, 6.47; N, 25.73.

Z-aminoisonicotinic acid 2-cycl0pentylhydrazide2- aminoisonicotinic acid 2-cyclopentylidenehydrazide (4.65 g., 0.0213 mole) was partially dissolved in 200ml. absolute ethanol with 1.0 g. platinum oxide, and the mixture shaken with hydrogen in a Parr apparatus at room temperature for one and one half hours. Slightly less than the theoretical amount of hydrogen was absorbed. The catalyst and undissolved starting material were filtered off and the solvent evaporated in vacuo to give 0.2 g. product, M.P. 170-175. The catalyst and unreacted starting material were washed with hot ethanol and the washings put back into the Parr apparatus with 500 mg. ffresh catalyst. The solution was then heated to 50 and again shaken with hydrogen. The calculated amount of hydrogen was absorbed. The catalyst was filtered off and the solvent evaporated in vacuo. The residue was recrystallized from absolute ethanol to yield 1.2 g., M.P. 175-177".

Analysis.Calcd. for C H N O: C, 59.98; H, 7.32; N, 25.44. Found: C, 59.83; H, 6.79; N, 24.81.

EXAMPLE 5 Z-aminoisonicotinic acid 2-cyclohexylidenehydrazine. 2-aminoisonicotinic acid hydrazide (6.0 g., 0.0395 mole) was refluxed for one hour with (5.0 g., 0.051 mole) cyclohexanone and 150 ml. absolute ethanol. The solution was cooled'and 7.2 g. (78.4%) product filtered 01f, M.P. 224-226". A second crop yielded 1.1 g. (total yield: 90.4%).

Analysis.Calcd. for C H N O: C, 62.05; H, 6.94; N, 24.12. Found: C, 61.65; H, 6.56; N, 24.33.

Z-aminoisonicotinic acid 2-cyclohexylhydrazide.2- aminoisonicotinic acid 2-cyclohexylidenehydrazide (7.0 g., 0.0302 mole) was partially dissolved in 250 ml. 2-methoxyethanol with 500 mg. platinum oxide, and the mixture shaken with hydrogen in a Parr apparatus at room temperature for two hours. Thehydrogen adsorption was slightly greater than the theoretical amount.

The catalyst was filtered off and the solvent evaporated in vacuo. The crude product was recrystallized from isopropyl alcohol to yield 3.0 g. (42.4%), M.P. 220- 223. The mixed melting point with starting material was 209-217. A second crop yielded 1.3 g. (total yield: 60.8%).

Analysis.Calcd. for C H N O: C, 61.51; H, 7.74; N, 23,92. Found: C, 61.43; H, 7.45; N, 23.90.

EXAMPLE 6 Z-aminoisonicotinic acid 2-(I-cyclopropylethylidene) hydrazide.2-aminoisonicotinic acid hydrazide (7.0 g., 0.0461 mole) was refluxed for seventeen hours with 12.6 g. (0.15 mole) methyl cyclopropyl ketone and 50 ml. absolute ethanol. After a small amount of insoluble material was filtered oil, the solution was evaporated to dryness in vacuo. The residue was recrystallized from ethyl acetate to yield 5.4 g. (53.7%) product, M.P. 158-459".

Analysis.Calcd. for C H N O: C, 60.53; H, 6.47; N, 25.67. Found: C, 60.42; H, 6.58; N, 25.80.

Z-amz'noisonicotinic acid 2-(] -cycl0pr0pylethyl) hydrazide.2-aminoisonicotim'c acid 2-(1-cyclopropylethylidene)hydrazide (4.9 g., 0.0225 mole) was partially dissolved in 200 ml. absolute ethanol with 500 mg. platinum oxide, and the mixture shaken with hydrogen in a Parr apparatus at room temperature for about three quarters of an hour whenthe hydrogen uptake stopped, although only one half the theoretical amount had been absorbed. 500 mg. more catalyst was added and the reaction mixture again shaken withhydrogen for two hours. During this second reaction period, the calculated amount of hydrogen was absorbed. The catalyst was filtered off and the solvent evaporated in vacuo. The crude product was recrystallized from absolute ethanol to yield 1.3 g. (26.3%), M.P. 167-169. Two more crops gave 2.2 g. (total yield: 70.7%) V Analysis.Calcd. for C H N O: C, 59.98; H, 7.32; N, 25.44. Found: C, 59.92; H, 7.64; N, 25.42.

When Z-aminoisonicotinic acid hydrazide isreactedaccording to the above procedures with the compounds listed below, and the resulting compounds hydrogenated, the products hereinafter set forthare obtained:

Cycloheptanone 2-arninoisonicotinic acid zcycloheptylhytlrazide.

Cyclooctanone 2ami.noisonicotinic acid Z-cyclooctylhydrazide.

Acetaldehyde 2-almintglisonicotinic acid 2-cthylhyraz1 e.

Propionaldehyde zaminoisonicotinie acid 2-pr0pylhydrazide.

Butyraldehyde 2-arninoisonic0tinic acid 2-butylhydrazide.

Gaprylaltlehyde 2-aminoisonicotinic acid 2-capry1- hydrazide.

3-pentanone Z-aminoisonicotinic aeid.2-(1-ethylpropyDhydrazide.

2-butanone 2-aminoisonicotinic acid Z-(I-methylpropyl)hydrazide.

Oyclopropyl ethyl ketone Z-aminoisonicotinic acid 2-(l-cycl0- propylpropyhhydrazide.

Cyclobutyl methyl ketone zaninoisonic'otinic acid 2-(1-cyclcbutylethybhydrazide.

Oyclobutyl ethyl kctone 2-aminois0nicotinic acid (2-(1-cyclobutylpropyl)hydrazide.

Cyclopentyl ethyl ketone 2-aminoisonic0tinic acid 2-(l-cycl0- pentylpropyhhydrazide.

Cyelopentylmethyl ketone Z-aminoisonicotinic acid 2-(1-cyclopentylethyl)hydrazide.

The compounds of this invention can be administered in a wide variety of oral or parenteral unit dosage forms, singly, or in admixture with other active compounds.

The present invention also includes the process of bringing the compounds thereof into a form suitable for therapeutic administration by associating them with liquid or solid, pharmaceutically acceptable carriers.

Various changes and modifications of this invention can be made by those skilled in the art to which it relates and to the extent that such variations incorporate the spirit of the invention, they are included in the scope of the claims.

What is claimed is:

1. A compound of the formula:

OONHNHR 8 carbon atoms in the ring and the 1-cycloalkylalkyl groups having a total carbon content ranging from 5 to I 8 carbon atoms.

2. A compoundrepresented by a formula selected from the group consisting of 6 and 9. Z-aminoisonicotinic acid 2-va1ery1hydrazide.

10. Z-aminoisonicotinic acid 2-cyclopenty1hydrazide.

11. Z-aminoisonicotinic acid 2-cyc1ohexy1hydrazide.

OONHN=O 12. 2-aminoisonicotinic acid 2-(1-cyclopr0py1ethy1)hy- 5 drazide.

NH References Cited in the file of this patent N 2 UNITED STATES PATENTS wherein n ranges from 4 to 7, R is a substituent selected 2,703,322 Fox Mar. 1, 1955 from the group consisting of lower alkyl having from one 10 2,767,192 Ofie et a1 Oct. 16, 1956 to 6 carbon atoms and cycloalkyl having from 3 to 5 carbon atoms and R is selected from nhe group consist- FOREIGN PATENTS ing of hydrogen and lower alkyl having from one to 2 726,230 Great Britain 1955 carbon atoms. 0TH R R FERENCE 3. Z-aminoisonicotinic acid 2-isopropy1idenehydrazide. E E S 4. Z-aminoisonicotinic acid 2-va1ery1idenehydrazide. Yale at JACS, VOL 751 Pages 1933-1942 5. 2-aminoisonicotinic acid 2-cyc1openty1idenehydra- 5;?) et 211-: chem-i Pages 9834-002 zide.

6. Z-aminoisonicotinic acid 2-cyclohexy1idenehydrazide. Abstraicmng Kaklmoto Japan 2, 7. 2 aminoisonicotinic acid 2 (1 cyclopropylethyl- 20 Pages 334-7 (1954)- idene)hydl-azide Stanoms: J. Org. Chem, vol. 22, page 475 (1957).

8. Z-aminoisonicotinic acid 2-isopropy1hydrazide. Chemical Abstracts, Pages 

1. A COMPOUND OF THE FORMULA: 